Immunosuppressive therapy of LGL leukemia: prospective multicenter phase II study by the Eastern Cooperative Oncology Group (E5998)

Abstract

Failure to undergo activation-induced cell death due to global dysregulation of apoptosis is the pathogenic hallmark of large granular lymphocyte (LGL) leukemia. Consequently, immunosuppressive agents are rational choices for treatment. This first prospective trial in LGL leukemia was a multicenter, phase 2 clinical trial evaluating methotrexate at 10 mg/m2 orally weekly as initial therapy (Step 1). Patients failing methotrexate were eligible for treatment with cyclophosphamide at 100 mg orally daily (Step 2). The overall response in Step 1 was 38% with 95% confidence interval (CI): 26%, 53%. The overall response in Step 2 was 64% with 95% CI: 35%, 87%. The median overall survival for patients with anemia was 69 months with a 95% CI lower bound of 46 months and an upper bound not yet reached. The median overall survival for patients with neutropenia has not been reached 13 years from study activation. Serum biomarker studies confirmed the inflammatory milieu of LGL but were not a priori predictive of response. We identify a gene expression signature that correlates with response and may be STAT3 mutation driven. Immunosuppressive therapies have efficacy in LGL leukemia. Gene signature and mutational profiling may be an effective tool in determining whether methotrexate is appropriate therapy.

Vitamin D decreases STAT phosphorylation and inflammatory cytokine output in T-LGL leukemia

“…38 Previous work by our laboratory and collaborators showed IFN-g is significantly upregulated in T-LGLL patient sera compared to normal donor sera, making this a plausible theory. 23 Second, constitutive activation of STAT1 in LGLL has previously been reported by our laboratory, as well as the possibility of STAT1-STAT3 heterodimer species. 5 It is plausible that VDR and STAT1 could interact in LGLL cells, given the high levels of each in most LGLL patients.…”

“…This mutation occurs in the Src homology 2 (SH2) domain, and was found to confer increased transcriptional activity 6 and correlated with a better therapeutic response to methotrexate therapy. 23 Therefore, we sought to correlate STAT3 Y640F mutation with the presence or absence of VDR. To accomplish this, we surveyed 5 WT STAT3 T-LGLL patients and 5 Y640F STAT3 T-LGLL patients (Fig.…”

LGL leukemia: from pathogenesis to treatment

“…The Eastern Cooperative Oncology Group prospective clinical trial suggested that a particular Stat3 mutation, Y640F, predicted response to initial therapy with methotrexate (MTX). 47 The first evidence of Stat5b mutations in human disease was discovered in LGL leukemia, but this mutation is not frequent (2%). 19 The N642H mutation in particular was associated with more aggressive disease and an unusual CD3 …”

“…This theory is supported by the observation that STAT3 mutations are correlated with a larger clone size in LGL leukemia patients. 47 Disease manifestations such as cytopenias and autoimmune diseases then result from the production of proinflammatory cytokines mediated by STAT 3 regulation, as well as attack on marrow and joints by the STAT 3-activated LGL. The key molecular signaling components in LGL leukemia are depicted in Figure 6.…”

“…60 We and others showed that LGL leukemia patients had increased serum levels of interferona2, monocyte chemoattractant protein-1 (an attractive factor of monocytes, T, and NK cells to sites of inflammation), epidermal growth factor, IL-6, IL-8, and IL-18. 47,61,62 High b2 microglobulin level is observed in 70% of cases. Rheumatoid factor and antinuclear antibody are detected in 60% and 40% of patients, respectively.…”